Abstract

Mutations in the KCNA1 gene are known to cause episodic ataxia/myokymia syndrome type 1 (EA1). Here, we describe two families with unique presentations who were enrolled in an IRB-approved study, extensively phenotyped, and whole exome sequencing (WES) performed. Family 1 had a diagnosis of isolated cataplexy triggered by sudden physical exertion in multiple affected individuals with heterogeneous neurological findings. All enrolled affected members carried a KCNA1 c.941T>C (p.I314T) mutation. Family 2 had an 8-year-old patient with muscle spasms with rigidity for whom WES revealed a previously reported heterozygous missense mutation in KCNA1 c.677C>G (p.T226R), confirming the diagnosis of EA1 without ataxia. WES identified variants in KCNA1 that explain both phenotypes expanding the phenotypic spectrum of diseases associated with mutations of this gene. KCNA1 mutations should be considered in patients of all ages with episodic neurological phenotypes, even when ataxia is not present. This is an example of the power of genomic approaches to identify pathogenic mutations in unsuspected genes responsible for heterogeneous diseases.

Pedigrees for families 1 and 2. a The affected proband (III:6), her affected brother (III:7) and mother (II:3), her two affected aunts (II:1 and II:2), and her four affected cousins (III:1, III:2, III:4, III:5) are shown along with their p.I314T variant status. b In family 2, the affected proband (II:1), his two unaffected parents (I:1 and I:2), and sibling (II:2) are shown along with the de novo variant p.T226R present in the proband. The square represents a male individual, a circle represents a female individual, and the arrow indicates the probands. Filled symbols represent clinically affected individuals

Molecular modeling of KCNA1 (KV1.1) variants. a Molecular structure of rat KCNA2 (KV1.2) (PDB code: 3LUT), a protein very similar to KCNA1, and for which crystal structure is available. The structural modeling and illustration were prepared by the software PyMOL (The PyMOL Molecular Graphics System, Version 1.7.4 Schrödinger, LLC). The channel forms a tetramer, with Thr226 residue in red and Ile314 colored in purple (marked by arrows). b, c WT Thr226 residue (b) and variant Thr226Arg (c) modeling. c The variant Thr226Arg conflicts with a Phe residue on the same helix (marked by arrow) and likely affects the hydrophobic packing with another helix through the interaction with the aromatic residues. d, e WT Ile314 residue (d) and variant Ile314Thr (e) modeling. e The variant Ile314Thr likely disrupts the hydrophobic packing between two transmembrane helices (marked by arrow)